Although all cells respond to oxidative stress and DNA damage with the induction of numerous genes, little is known about the underlying mechanisms involved in these responses in eucaryotes. GADD153 is a CCAAT/enhancer-binding protein (C/EBP)-related gene that is rapidly and highly induced in response to a variety of stresses including DNA damage and oxidative stress and provides a useful model for examining the molecular mechanisms involved in eliciting the response to gentoxic stress. It is a putative negative regulator of other C/EBP transcriptional activators, and as such could play a key role in determining what other genes are expressed or repressed in response to these stresses. Our recent studies have concentrated on the pathways mediating the induction of GADD153 in response to DNA damage and oxidative stress. In contrast to transcriptional activation of other DNA damage inducible genes, GADD153 induction appears to involve neither protein kinase C nor tyrosine kinases, but rather requires an unidentified serine-threonine kinase, thus representing a unique pathway in the cellular response to gentoxic stress. In addition, based on their relative sensitivity to cellular levels of glutathione, it appears that oxidative stress and DNA damage regulate transcription through different pathways. Using gel mobility shift assays we have identified several cis elements in the promoter region of the GADD153 which show enhanced binding to factors present in nuclear lysates prepared from cells treated with DNA damaging agents. These are likely to represent binding of transcription factors important in mediating the gene's transcriptional activation in response to the stress. To explore the relationship between DNA damage and/or repair capacity and the expression of GADD153 we examined the activation of the GADD153 promoter in cisplatin-resistant versus cisplatin resistant HeLa cells following their treatment with the genotoxic agent. We observed lower GADD153 expression in the resistant cells relative to the sensitive cells from which they were derived. These findings support the notion that the expression of GADD153 is related to the cell's sensitivity to cytotoxic effects of the DNA damaging agent.